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Agents for Promoting the Growth of Hematopoietic Stem Cells

a technology of stem cells and agents, applied in the direction of antibody medical ingredients, drug compositions, extracellular fluid disorders, etc., can solve the problems of not reporting whether cd34-positive cells survive, or mention human cord blood, etc., to promote the growth of cd34-positive hematopoietic cells, enhance the engraftment of transplanted cells, and induce significant growth

Inactive Publication Date: 2010-02-18
CHUGAI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention relates to agents that promote the growth and differentiation of hematopoietic stem cells, as well as agents that enhance the engraftment and recovery of hematopoietic cells after transplantation. The agents comprise an agonist for the TPO receptor (c-mpl), which is a specific receptor that promotes the growth and differentiation of megakaryocytic lineage cells. The invention is based on the discovery that antibodies with TPO receptor agonist activity can successfully activate the growth of hematopoietic stem cells, and the use of such agents has been reported in various animal models and in humans. The technical effects of the invention include the promotion of hematopoietic stem cell growth and differentiation, as well as the enhancement of engraftment and recovery of hematopoietic cells after transplantation.

Problems solved by technology

However, it does not report whether grafted CD34-positive cells survive, or mention human cord blood.

Method used

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  • Agents for Promoting the Growth of Hematopoietic Stem Cells
  • Agents for Promoting the Growth of Hematopoietic Stem Cells
  • Agents for Promoting the Growth of Hematopoietic Stem Cells

Examples

Experimental program
Comparison scheme
Effect test

example 1

Effect of the TPO Receptor Agonist on the Engraftment Number of Different Human Blood Cell Lineages in the Bone Marrow of Mice Transplanted with Human Cord Blood-Derived Hematopoietic Stem Cells

[0149]The experiments were carried out by the method described below to assess the effect of the sc(Fv)2 antibody (hVB22 u2-wz4: sc(Fv)2) comprising the amino acid sequence of SEQ ID NO: 73 on the engraftment number of different human blood cell lineages in the bone marrow of mice transplanted with human cord blood-derived hematopoietic stem cells at early stages. The sc(Fv)2 antibody comprising the amino acid sequence of SEQ ID NO: 73 can be prepared by the method described in WO 2005 / 056604.

Methods

[0150]Mice used were acclimatized six-week-old male NOD.CB17-Prkdc / J. After systemic irradiation with 3.0 Gy of X-ray, an anti-asialo-GM1 antibody was intraperitoneally administered to the mice once every ten days from the day of irradiation. 5×104 human cord blood-derived CD34-positive cells were...

example 2

Effect of the TPO Receptor Agonist on the Number of Human CFU-Meg Colonies in the Bone Marrow of Mice Transplanted with Human Cord Blood-Derived Hematopoietic Stem Cells

[0152]The following experiments were carried out to assess the effect of the sc(Fv)2 antibody of SEQ ID NO: 73 on the number of human CFU-Meg colonies after transplantation of human cord blood-derived hematopoietic stem cells.

Methods

[0153]Mice used were acclimatized six-week-old male NOD.CB17-Prkdc / J. After systemic irradiation with 3.0 Gy of X-ray, an anti-asialo-GM1 antibody was intraperitoneally administered to the mice once every ten days from the day of irradiation. 5×104 human cord blood-derived CD34-positive cells were transplanted to each mouse at the caudal vein one day after irradiation. From the day after transplantation, the sc(Fv)2 antibody of SEQ ID NO: 73 was administered every day for ten consecutive days, and then after that, administration was conducted for five days followed by two days of break. T...

example 3

Dose-Dependent Effect of the TPO Receptor Agonist on the Engraftment Number of Different Human Blood Cell Lineages in the Bone Marrow of Mice Transplanted with Human Cord Blood-Derived Hematopoietic Stem Cells

[0155]The following experiments were carried out to assess the dose-dependent effect of the sc(Fv)2 antibody of SEQ ID NO: 73 on the engraftment number of different human blood cell lineages in the bone marrow of mice transplanted with human cord blood-derived hematopoietic stem cells.

Methods

[0156]Mice used were acclimatized six-week-old male NOD.CB17-Prkdc / J. After systemic irradiation with 3.0 Gy of X-ray, an anti-asialo-GM1 antibody was intraperitoneally administered to the mice on the day of irradiation and eight days after irradiation. 5×104 human cord blood-derived CD34-positive cells were transplanted to each mouse at the caudal vein the day after irradiation. The sc(Fv)2 antibody of SEQ ID NO: 73 was administered every day for ten consecutive days from the day after the...

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Abstract

The present inventors discovered that the administration of an agonistic minibody (VB22B sc(Fv)2) against the TPO receptor resulted in not only the induction of human megakaryocyte-specific differentiation (increase in platelet precursor cells), but also the engraftment of transplanted hematopoietic stem cells derived from human cord blood (CD34-positive cells) and significant increase in multi-lineage hematopoietic precursor cells. TPO and TPO receptor agonists can be used as agents for promoting the growth of CD34-positive hematopoietic cells or agents for promoting the engraftment of transplanted cells in the bone marrow, which can be effective when administered alone (without using G-CSF and erythropoietin in combination) after hematopoietic stem cell transplantation (in particular, cord blood transplantation). Furthermore, TPO and TPO receptor agonists can be used as agents for promoting the growth and / or differentiation of multilineage hematopoietic precursor cells and agents for promoting the recovery of multilineage hematopoiesis.

Description

TECHNICAL FIELD[0001]The present invention relates to agents for promoting the growth of hematopoietic stem cells, which comprise an agonist for the TPO receptor (c-mpl) as an active ingredient. The present invention also relates to agents for promoting the growth and / or differentiation of CD34-positive hematopoietic cells, agents for promoting the engraftment of CD34-positive hematopoietic cells transplanted in the bone marrow, and agents for promoting the recovery of hematopoiesis after hematopoietic stem cell transplantation, wherein the agents comprise an agonist for the TPO receptor (c-mpl) as an active ingredient.BACKGROUND ART[0002]Thrombopoietin (TPO) is a cytokine that promotes the growth and differentiation of megakaryocytic lineage cells, and is known as a megakaryocyte colony-stimulating factor and a ligand for c-mpl. Upon ligand binding, most cytokine receptors dimerize to transduce signals into cells. It has been reported that TPO binds to its specific receptor, c-mpl,...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/395A61K35/12A61K39/00
CPCA61K2039/505C07K16/2866C07K2317/52C07K2319/00C07K2317/74C07K2317/622A61P35/00A61P35/02A61P43/00A61P7/00A61P7/06A61K39/395
Inventor YOSHIKUBO, TAKASHISHIINA, MASASHIINAGAKI, YUKIKO
Owner CHUGAI PHARMA CO LTD
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